The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates
Authors: Claudia Buhigas, Anne Y. Warren, Wing-Kit Leung, Hayley C. Whitaker, Hayley J. Luxton, Steve Hawkins, Jonathan Kay, Adam Butler, Yaobo Xu, Dan J. Woodcock, Sue Merson, Fiona M. Frame, Atef Sahli, Federico Abascal, Abraham Gihawi, Adam Lambert, Alan Thompson, Andrew Futreal, Andrew Menzies, Anne Baddage, Anthony Ng, Atef Sahil, Barbara Kremeyer, Bissan Al-Lazikani, Charlie Massie, Christopher Greenman, Christopher Ogden, Clare Verrill, Cyril Fisher, Dan Berney, Dan Burns, Daniel Leongamornlert, David Jones, David Nicol, David Wedge, Declan Cahill, Douglas Easton, Edward Rowe, Ekaterina Riabchenko, Elizabeth Bancroft, Erik Mayer, Ezequiel Anokian, Freddie Hamdy, Gahee Park, Gill Pelvender, Gregory Leeman, Gunes Gundem, Hongwei Zhang, Ian G. Mills, Jingjing Zhang, Jon Teague, Jorge Zamora, Katalin Karaszi, Kieran Raine, Lucy Matthews, Lucy Stebbings, Ludmil B. Alexandrov, Luke Marsden, Mahbubl Ahmed, Matti Nykter, Mohammed Ghori, Naomi Livni, Nening Dennis, Nicholas Van As, Niedzica Camacho, Nimish Shah, Pardeep Kumar, Peter Van Loo, Radoslaw Lach, Sandra Edwards, Sara Pita, Sarah J. Field, Sarah Thomas, Simon Tavaré, Stefania Scalabrino, Steven Hazell, Stuart McLaren, Tapio Visakorpi, Thomas J. Mitchell, Tim Dudderidge, Tokhir Dadaev, Ultan McDermott, Valeria Bo, Valeriia Haberland, Vincent Gnanapragasam, Vincent Khoo, William Howat, Yong Jie-Lu, Yongwei Yu, Zsofia Kote-Jarai, Iñigo Martincorena, G. Steven Bova, Christopher S. Foster, Peter Campbell, Norman J. Maitland, David E. Neal, Charlie E. Massie, Andy G. Lynch, Rosalind A. Eeles, Colin S. Cooper, David C. Wedge, Daniel S. Brewer
Journal: Molecular Cancer (2022)

Abstract Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue ( n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results Single nucleotide variants ( P = 7.0 × 10 –03 , Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10 –06 ) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer ( P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial ( P = 5.94 × 10 –05 , paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants ( P = 3.72 × 10 –09 , paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.